VCP/p97 in abnormal protein aggregates, cytoplasmic vacuoles, and cell death, phenotypes relevant to neurodegeneration
VCP/p97 in abnormal protein aggregates, cytoplasmic vacuoles, and cell death, phenotypes relevant to neurodegeneration
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DOI：
10.1038/sj.cdd.4400907
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发表时间：
2001-10-01
影响因子：
12.4
通讯作者：
Kakizuka, A
中科院分区：
文献类型：
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作者：
Hirabayashi, M;Inoue, K;Kakizuka, A
神经元细胞死亡、异常蛋白质聚集体和胞质空泡化是在许多神经退行性疾病如多聚谷氨酰胺（polyQ）疾病、朊病毒病、阿尔茨海默病和路易体疾病中观察到的主要病理，表明神经退行性疾病的共同机制。在这里，我们已经确定了VCP/p97，AAA+家庭的ATP酶蛋白的成员，作为一个polyQ相互作用的蛋白质在体外和体内，并报告其表征。内源性VCP与表达ex-polyQ的培养细胞中的扩增polyQ（ex-polyQ）聚集体、与亨廷顿病患者脑中的核包涵体以及与患者样品中的路易体共定位。此外，在第二ATP结合结构域中具有突变的VCP突变体的表达产生细胞质空泡，随后细胞死亡。非常相似的空泡也诱导前polyQ表达或蛋白酶体抑制剂治疗。这些结果表明，VCP的功能不仅作为一个识别因子的异常折叠的蛋白质，但也作为一个病理效应的几种神经退行性表型。因此，VCP可能是治疗神经退行性疾病的理想分子靶点。
Neuronal cell death, abnormal protein aggregates, and cytoplasmic vacuolization are major pathologies observed in many neurodegenerative disorders such as the polyglutamine (polyQ) diseases, prion disease, Alzheimer disease, and the Lewy body diseases, suggesting common mechanisms underlying neurodegeneration. Here, we have identified VCP/p97, a member of the AAA+ family of ATPase proteins, as a polyQ-interacting protein in vitro and in vivo, and report on its characterization. Endogenous VCP co-localized with expanded polyQ (ex-polyQ) aggregates in cultured cells expressing ex-polyQ, with nuclear inclusions in Huntington disease patient brains, and with Lewy bodies in patient samples. Moreover, the expression of VCP mutants with mutations in the 2nd ATP binding domain created cytoplasmic vacuoles, followed by cell death. Very similar vacuoles were also induced by ex-polyQ expression or proteasome inhibitor treatment. These results suggest that VCP functions not only as a recognition factor for abnormally folded proteins but also as a pathological effector for several neurodegenerative phenotypes. VCP may thus be an ideal molecular target for the treatment of neurodegenerative disorders.